title: Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes.
abstract: Irinotecan (CPT-11) is a promising antitumor agent, recently approved for use in patients with metastatic colorectal cancer. Its active metabolite, SN-38, is glucuronidated by hepatic uridine diphosphate glucuronosyltransferases (UGTs). The major dose-limiting toxicity of irinotecan therapy is diarrhea, which is believed to be secondary to the biliary excretion of SN-38, the extent of which is determined by SN-38 glucuronidation. The purpose of this study was to identify the specific isoform of UGT involved in SN-38 glucuronidation. In vitro glucuronidation of SN-38 was screened in hepatic microsomes from normal rats (n = 4), normal humans (n = 25), Gunn rats (n = 3), and patients (n = 4) with Crigler-Najjar type I (CN-I) syndrome. A wide intersubject variability in in vitro SN-38 glucuronide formation rates was found in humans. Gunn rats and CN-I patients lacked SN-38 glucuronidating activity, indicating the role of UGT1 isoform in SN-38 glucuronidation. A significant correlation was observed between SN-38 and bilirubin glucuronidation (r = 0.89; P = 0.001), whereas there was a poor relationship between para-nitrophenol and SN-38 glucuronidation (r = 0.08; P = 0.703). Intact SN-38 glucuronidation was observed only in HK293 cells transfected with the UGT1A1 isozyme. These results demonstrate that UGT1A1 is the isoform responsible for SN-38 glucuronidation. These findings indicate a genetic predisposition to the metabolism of irinotecan, suggesting that patients with low UGT1A1 activity, such as those with Gilbert's syndrome, may be at an increased risk for irinotecan toxicity.
authors.affiliation: Committee on Clinical Pharmacology, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: L
authors.initials: L
authors.lastname: Iyer
authors.forename: C D
authors.initials: CD
authors.lastname: King
authors.forename: P F
authors.initials: PF
authors.lastname: Whitington
authors.forename: M D
authors.initials: MD
authors.lastname: Green
authors.forename: S K
authors.initials: SK
authors.lastname: Roy
authors.forename: T R
authors.initials: TR
authors.lastname: Tephly
authors.forename: B L
authors.initials: BL
authors.lastname: Coffman
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism; D015984:Causality; D003414:Crigler-Najjar Syndrome / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D009596:Nitrophenols / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014530:Uridine Diphosphate; D015215:Zidovudine / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007527:Isoenzymes; D009596:Nitrophenols; C064976:O(6)-benzylguanine; D015215:Zidovudine; D014530:Uridine Diphosphate; D006147:Guanine; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D001663:Bilirubin; D002166:Camptothecin; C024836:4-nitrophenol